A general procedure is outlined for studying the binding of electrophiles, particularly heavy metal species, to polynucleotides and nucleic acid constituents in aqueous solution. The principal experimental technique employed is Raman difference spectroscopy augmented by Fourier transform infrared and 1H NMR spectroscopy. Structures of products produced by attack on a nucleoside are determined by comparison of the spectra with those of model compounds of known structure. The spectra provide fingerprints for identification of the products in more complex systems. By studying the reactions over a wide range of reactant concentrations and pH, the equilibrium constants can be determined by the proton competition method. Data also are obtained on the inductive effect of the bound electrophile. The rate of electrophilic attack also can be measured with inert systems. Selectivity in the attack on a mixture of several nucleotides is studied by the competitive reaction technique. Model systems consisting of four nucleotides or the corresponding phosphate methyl esters are allowed to compete for a limited amount of electrophile. The product distribution in labile systems is determined with the aid of the Raman, IR, and 1H NMR fingerprints. In this way, the effect of changes in metal electronic configuration and the other ligands in the coordination sphere on selectivity can be measured, and metal electrophiles can be compared with alkylating agents. We propose to compare, particularly, the very labile H3CHg(II) and (H3C)2Au(III), the moderately reactive enPdCl2 (en equals ethylenediamine), trans-(H3N)2PdCl2, (Co(NH3)5OH2)3 ion, and the inert enPtCl2, trans-(H3N)2PtCl2, and H3CSO2OCH3. Competition among sites on a polynucleotide can be studied by the Raman and ir techniques and compared to the model system with similar base composition. Improvements in Raman difference spectrophotometry for the study of reactions of biological molecules in aqueous solution are described.